The regulation of leukocyte adhesion to endothelial cells is an essential and complex aspect of leukocyte migration and host defense. The ability of leukocytes to migrate into areas of inflammation is critical for the generation of an immune response. The studies will examine the molecules that mediate the interactions between leukocytes and endothelial cells, focusing specifically on L-selectin, a member of the selectin family of cellular adhesion molecules. L-selectin plays a critical role in lymphocyte migration by mediating binding to the high endothelial venules of peripheral lymph nodes, and mediates leukocyte rolling along the vascular wall at sites of inflammation. L-selectin is unique among adhesion receptors since it is endoproteolytically released from the cell surface immediately following cellular activation, a process that is likely to also regulate leukocyte migration. We have made considerable progress over the last five years in showing that L-selectin is a major leukocyte adhesion molecule. Our studies with L-selectin deficient mice support this conclusion and have demonstrated that L-selectin contributes substantially during inflammatory conditions such as septic shock and delayed-type hypersensitivity reactions. The proposed studies will further expand upon our knowledge of the role of L-selectin in leukocyte adhesion and how L-selectin interacts with other adhesion molecules and regulates their function with the specific aims of: 1) using adhesion receptor-deficient mice to further characterize the in vivo role of L- selectin and other adhesion receptors in normal leukocyte migration, and during acute and chronic inflammation; 2) determining the biological significance of endoproteolytic release of L-selectin from the cell surface; 3) determining the biological significance of L-selectin mediated signal transduction and whether there is cross-talk between L-selectin, chemokine receptors and integrins during leukocyte/endothelial interactions; and 4) characterizing the ligand(s) for L-selectin induced on vascular endothelial cells. In addition to providing a clearer understanding of the molecular events that regulate leukocyte migration, these studies will also identify targets for therapeutic intervention and generate biological reagents with clinical utility. These reagents may prove applicable to the treatment of a broad array of human disorders such as preventing lethal septic shock or blocking the dissemination of certain lymphoid tumors. Finally these studies will also provide a solid basis for understanding the mechanisms by which L-selectin, other adhesion receptors or biologic response modifying agents, such as chemokines are able to dramatically alter leukocyte migration in patients with cancer or acute and chronic inflammatory disorders.